Dermatogenetics

We are interested in the molecular basis for genetic skin and hair diseases. We have particularly focused on the molecular mechanisms that regulate the epidermal differentiation and the interaction of genes and gene products underlying epidermal pathology, which is a prerequisite for identifying novel approaches into the therapeutic intervention.

In recent years the molecular causes for several genetic skin diseases have been identified. However, still only few is known about the interaction of proteins specific to epidermal keratinocytes and their role in disease mechanisms. This is of particular importance with regard to the extended clinical and genetic heterogeneity of monogenic skin disorders. We have been analysing autosomal recessive congenital ichthyosis (ARCI), which can be caused by mutations in the genes TGM1, ALOX12B, ALOXE3, Ichthyin, ABCA12, and CYP4F22, and for which mutations in even further genes must exist. The positional cloning approach using linkage analysis and especially autozygosity mapping with consanguineous families is promising to identify new loci underlying the disease.

A clear genotype/phenotype correlation has not yet been found in ARCI. Moreover, the disease mechanisms underlying the development of congenital ichthyosis are mostly unknown. Whereas transglutamianse 1, encoded by TGM1, plays a decisive role in the formation of the cornified cell envelope, at least 12R-LOX and eLOX-3, encoded by ALOX12B and ALOXE3, take part in the 12-lipoxygenase pathway metabolizing arachidonic acid in epidermal keratinocytes. In order to characterize this pathway, we have established 3D skin models for congenital ichthyosis and are comparing these with a new animal model with a defective 12-lipoxygenase pathway.

Few is known about the molecular basis for multifactorial skin and hair disorders. We are interested in the pathology of alopecia areata, a frequent and often chronic disorder of the hair follicle with a strong genetic susceptibility towards autoimmune disease. The genetic basis is completely unknown and genetic factors involved have not been identified in a systematic approach so far. We are using a concerted strategy of characterizing the basis for hair loss in an established animal model, the Dundee epidermal bald (DEB) rat, and searching genetic factors underlying susceptibility to alopecia areata in humans primarily using an affected sib pair study design. A long-term goal of these investigations is to identify novel approaches into causative therapy and develop specific drugs to combat hair loss.